Sean Milmo is a freelance writer based in Essex, UK.

Sean Milmo

The drive to embed quality-by-design (QbD) principles into the pharmaceutical regulatory framework of the European Union has reached a key point 10 years after the European Medicines Agency (EMA) first backed QbD concepts. A relatively small number of marketing approval applications made in Europe have supporting QbD data, with EMA conceding that application dossiers with QbD information are far from becoming a standard approach. Nonetheless, the pharmaceutical industry has been internally adopting the QbD concepts laid down in the guidelines of the International Conference on Harmonization (ICH) covering pharmaceutical development (Q8), quality risk management (Q9), pharmaceutical quality systems (Q10), and the development and manufacture of drug substances (Q11) (1-4).

The international pharmaceutical companies in particular have benefited from applying QbD principles to their manufacturing operations. These companies have seen increased production efficiencies and yields as a result, with fewer off-specification outputs and a decrease in production recalls. Some of the leading pharmaceutical companies have been pace setters in including QbD data in authorization dossiers for approval of new medicines. Most pharmaceutical manufactures, however, have been reluctant to tie their marketing-authorization applications to this higher standard of quality management.


QbD is now at a “critical step” between regulatory support for its concepts and a much deeper implantation of its principles, Georges France, external relations head of quality at Novartis, noted at a joint quality-by-design workshop of EMA and Parenteral Drug Association (PDA) in London in late January 2014. According to France, the next step involves a streamlined system of regulatory review of QbD applications that needs to be extended to a “global regulatory alignment.” 

The workshop, which included participants from FDA and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), revealed that there are, however, a number of big hurdles to widespread adoption of QbD despite considerable progress in its acceptance by the industry in recent years. One of the speakers at the meeting, Christine Moore, acting director of FDA’s Office of New Drug Quality Assessment (ONDQA), summarized the main concerns as being the classifying of criticality, levels of details required in process descriptions and in risk assessments, design-space verification, and changes to non-critical process parameters (non-CPPs).

Other major issues emerging at the conference, which focused on six case studies of QbD submissions evaluated by EMA, included real-time release testing (RTRT), application of QbD to continuous manufacture and biopharmaceutical production, dealing with post-approval changes to QbD processes, and the need for international harmonization of assessment methods. Regulators at the meeting complained that one big difficulty comes from the differences in terminology as well as the definitions used by pharmaceutical companies in their submissions, or during consultations on QbD matters.

“We have dealt with doubts about the terminology of terms by asking companies to verify what they mean before we review submissions,” commented one regulator speaking from the floor. “But the use of different definitions by companies for the same terms is something that should be sorted out between regulators.”

Some differences in terminology appear to have stemmed from companies adopting QbD concepts internally to gain greater operational efficiencies but in the absence of making QbD submissions with marketing-authorization applications, some of these companies have lost touch with the terminology in the ICH QbD guidelines.


In a QbD dossier drawn up by GlaxoSmithKline (GSK), which was the subject of a case study presented at the meeting, the company used terms created before the ICH guidelines were finalized. As a result, “ICH terminology was not always followed, which in some situations, made it difficult to follow the information in the dossier in relation to guideline requirements,” said Gorm Herlev Joergensen, head of pharmabiotech, Danish Health and Medicines Authority, and Theodora Kourti, senior technical director, GSK, who jointly presented the case study (5). With some aspects of QbD, the ICH guidelines do not provide definitions. Non-CPPs, for example, are not defined in the guidelines. 

Regulators at the meeting also stressed the need for QbD submissions to provide sufficient data for the sake of clarity and also to enable companies to justify properly the adoption of certain approaches to quality issues. The GSK dossier was praised by its regulatory assessors for the thoroughness of the data provided. The assessors, however, warned about the inclusion of complex statistical calculations in QbD submissions for this case study. 

According to the case study, evaluation of statistical calculations, such as multivariate analysis, and the choice of experimental models on which QbD approaches are based, are challenging and require advanced statistical knowledge. Common quality assessors and GMP inspectors, however, usually do not have such knowledge, the study noted. 


Both regulators and industry executives at the meeting conceded that QbD requires more resources to gather extra data and to answer the questions triggered by the data. This is particularly the case when drawing up design spaces that set the combination of variables and process parameters needed to ensure quality but have to be based on a scientific understanding of how these factors interact.

As a result, “industry experience to date suggests that design spaces for more complex products (e.g., biopharmaceuticals) may be harder to get approved,” said Tone Agasoester of the Norwegian Medicines Agency and Graham Cook, senior director, process knowledge/quality by design at Pfizer, in a joint presentation on design space verification (6).

A key issue with design spaces is that they are often developed at a small scale at the laboratory or pilot level. Despite that, design spaces have to show that they match the quality requirements needed at commercial scale. The incentive behind the resources devoted to design space development is the greater operating flexibility they allow in the post-approval phase so that process variations do not have to be authorized. 


Process innovation with a greater assurance of quality is a driving force behind QbD but it has to have the support of a simplified procedure for the approval of variations. “We need to be more innovative if we are to be successful in delivering consistent and reliable quality for all products,” said David Tainsh, chief product quality officer at GSK, and Keith Pugh, expert pharmaceutical assessor at the UK Medicines and Healthcare products Regulatory Agency (MHRA), in a joint presentation on innovation (7). The barriers to innovation include limited availability of new skillsets, an unwillingness to deploy new technology, perceptions of high regulatory hurdles, and the absence of a procedure to manage complex lifecycle management changes, said the speakers. Above all, they added that there is “a lack of an overall vision on how to modernize pharmaceutical manufacture.”

Among the novel products to which QbD principles are having to be applied are advanced therapeutics, oligonucleotides, and microneedles, while innovative methods of manufacture and control include continuous processing, synthetic biochemistry, discrete manufacture, and analytics. Tainsh and Pugh cited, as an example of innovation, liquid dispensing with process analytical technologies (PAT), such as near infrared (NIR) inspection, ultraviolet (UV) solution analysis, droplet weight checks, and pad inspections. The future “desired state” would be an enabling regulatory strategy and a procedure that keeps pace with innovation with increased scientific dialogue between regulators and industry. It would even include regulators being trained in new skillsets. There would also have to be “enhanced scientific and risk-based approaches to QbD to match new technologies with a simplified and streamlined variations process,” said Tainsh and Pugh.

There have been signs of an acceleration in the numbers of QbD submissions. Yoshihiro Matsuda, of the PMDA’s office of standards and guidelines development, told the meeting that after averaging approximately three QbD applications annually for a few years, the number jumped to 11 submissions per year in 2011-2012 and to six submissions up to mid-2013. EMA has reported that after averaging approximately five submissions per year since 2008, QbD applications went up to eight submissions last year. The rise in QbD applications from a low base could be evidence of more pharmaceutical innovations stimulating a higher uptake of QbD principles. There is, however, still a long way to go in Europe before QbD principles are firmly incorporated into regulatory procedures. 
  
  

 Step 4 version (August 2009).
  2. 	ICH, Q9 

 Step 4 version (November 2005).
  3. 	ICH, Q10 

, Step 4 version (June 2008).
  4.	ICH, Q11 

Development and Manufacture of Drug Substances

, Step 4 version (May 2012). 
  5. 	G.H. Joergensen and T. Kourti, 

Case Study 4: Challenge of implementation of model-based and PTA-based RTRT for new products

, presentation at EMA-PDA QbD Workshop (London, Jan. 2014).
  6. 	T. Agasoester and G. Cook,

 Case Study 2: Development and verification of design space

, presentation at EMA-PDA QbD Workshop (London, Jan. 2014). 
7. 	D. Tainsh and K. Pugh, 

Innovation in medicines and manufacturing, future opportunities

, presentation at EMA-PDA QbD Workshop (London, Jan. 2014). 


Sean Milmo is a freelance writer based in Essex, UK, 

Articles

As Europe strives to firmly incorporate quality-by-design principles, there are several key issues that still need to be addressed.

Quality by Design&#151;Bridging the Gap between Concept and Implementation

Compliance with European Union rules on the security of medicines packaging, the last aspect of the EU’s Falsified Medicines Directive (FMD) to come into effect, is now looking likely to be a daunting task for many pharmaceutical manufacturers. A few key items of the required security features have just been revealed by the European Commission, the EU’s Brussels-based executive, although the drawing up of the rules is not due to be completed until the end of the year.  Manufacturers will then have three years to prepare for the deadline for their implementation.

The FMD, which was approved in 2011, was introduced to combat the rising number of falsified medicines in the EU. In 2011, almost 30 million counterfeit medicines were seized at EU borders. Meanwhile other important parts of the FMD—like quality controls on imported APIs, regulation of Internet supplies, and strengthening of requirements for wholesalers—are already coming into effect.


Obligatory safety features on medicines packaging, which enable the verification of the authenticity of the pharmaceuticals along the supply chain through a unique identifier on each pack, are turning out to be one of the most complex provisions of the legislation. The Commission has been delegated to draft the packaging rules after a lengthy consultation exercise among stakeholders. Generic medicines manufacturers have, for example, wanted to be excluded from the principal requirements because of the additional production costs for protecting low-cost drugs that are unlikely to be falsified.

 “What’s clear now is that the rules will bring in one of the biggest production changes in the pharmaceutical industry for a long time because for the first time there will be a need to have a unique identifier code on each pack,” explains Craig Stobie, global life sciences manager at Domino Printing Sciences, Cambridge, England, a leading player in the global coding and printing technologies sector for pharmaceuticals. 

Among the details of the packaging rules revealed by the commission in January was that the unique identifier would be placed in a 2D barcode. It will comprise a manufacturer code, a serialization number, a national reimbursement number (if necessary), the batch number, and the expiry date.

The medicine authenticity would be guaranteed by an end-to-end verification system so that the drug pack would be scanned at the pharmacy or other dispensing points. Medicines at higher risk of falsification, such as returns or medicines not being distributed directly by manufacturers, will be additionally checked at the wholesaler level.  

The nature of the anti-tamper device on each pack will be left to the choice of manufacturers. Also the commission has decided that all prescription medicines, with a few minor exceptions, would have to carry the unique identifier code, including generic drugs.

“The implementation of safety features will add significant costs for low-priced medicines even though only 0.005% of medicines in the EU legal supply chain are alleged to be falsified,” says Maarten van Baelen, medical affairs manager at the European Generic Medicines Association (EGA), Brussels, representing generics manufacturers. 

“The EGA has calculated that the upgrading of packaging lines to adopt the Falsified Medicines Directive fully would cost the EU generic medicines industry €1 billion,” he added in an interview with 

The exclusion of generic drugs from the unique identifier system is not supported by most other sectors in the European pharmaceutical industry. The European Federation of Pharmaceutical Industries and Associations (EFPIA), Brussels, the main body representing research-based pharmaceutical companies, strongly favors all prescription-only medicines being subject to the same level of security. It argues that introducing safety features on some prescription medicines would shift the threat to those not protected, which would defeat the aim of eliminating the whole counterfeiting problem.

Allowing some products to be unprotected by the unique identifier feature was also sharply criticized by the European Directorate for the Quality of Medicines and Healthcare (EDQM). Such a step would undermine a major objective of the FMD to improve the efficiency of the whole pharmaceutical supply chain throughout Europe, claimed the EDQM, which is part of the Council of Europe and responsible for the 


Both organizations want an approach that achieves as much harmonization as possible in Europe’s highly complex medicines supply chain. In the 36 countries the EDQM covers, including the EU’s 28 members states, EDQM calculates that there are 17,000 pharmaceutical manufacturers, 22,000 wholesalers and distributors, 170,000 retail pharmacies, 6500 hospital pharmacies, and 4000 internet/mail-order pharmacies.

Both EFPIA and EDQM are involved in the development of separate coding and serialization systems for application across Europe. Along with the main European associations for pharmaceutical wholesalers, parallel traders and distributors and community pharmacists, EFPIA has helped set up the European Stakeholder Model (ESM), which has been undergoing trials in parts of Europe.

“EFPIA has already seen great progress in trials run thus far and is optimistic about the ESM’s ability to advance the EU’s anti-counterfeiting measures,” Andreas Walter, EFPIA’s serialization project director, told Pharmaceutical Technology.  In guidance issued to its members in November 2013, the association has told its members to start immediately preparation for compliance with the FMD rules on packaging.

“Overall we can conclude that early adopters--those who comply sooner with the FMD in the ESM framework--have a definite advantage,” Walter says. “If everyone starts at the same time after publication of (the rules), there will be a problem with the availability of service providers for the packaging lines, which must all be modified in only three years.”

The EGA has pointed out the difficulties of upgrading an estimated 10,000 packaging lines serving the European generics market, which accounts for half of all pharmaceutical sales by volume. “In order to ensure continuity of supply of medicines, it is necessary to upgrade lines in a highly controlled manner,” says van Baelen. “Commercial providers of printers, scanners, and serialization software have expressed concerns that they will not have the hardware and human resources to upgrade all these lines by 2018.”

The EGA is calling for a phased-in approach to the implementation of the serialization rules, starting with high-priced and other products with the most risk of falsification.

“By starting small and solving any arising complications on a small scale, continuity of supply of affordable medicines will be less at risk, much of the cost can be spread over time, and the credibility of the control system can be maintained,” explains van Baelen.


In ESM coding guidelines published last June, EFPIA warned that the success or failure of its system would be determined by the printing quality of the codes. “In addition to selecting the most appropriate printing technology, this requires manufacturers to ensure that the pack carton is suitable,” EFPIA says. “(This means ensuring) that the appropriate substrate is selected, that varnish-free areas are available, and that there is enough free space on the artwork.”

Domino stresses that the quality of the printing of the code can depend on a number of players in the supply chain, which will now have to work together effectively to enable the end-to-end verification of a unique identifier system to operate properly. “The supply chain can include not just the ink producers and the manufacturers of the inkjet or laser equipment but also the makers of the cartons and the carton board,” says Stobie.  “If the carton board is not white enough the ink may have insufficient clarity and blackness.”

The quality of the ink and printing will be crucial for products, which could be in the supply chain for as long as two years because of Europe’s intricate distribution network for medicines. “If ink deteriorates due to high or low temperatures or moisture in storage facilities the scanning of individual products at the dispensing point in pharmacies will fail,” Stobie explains.

The FMD serialization scheme when it is operating fully will be scanning 17 billion prescription medicines per annum, according to EGA estimates.  “A 0.1% error rate would equal 17 million undispensed boxes per year or 46,575 boxes per day,” says van Baelen. “One third of pharmacies in Europe would see an error per day.”

Tests of a serialization system called securPharm in Germany, which involves 400 pharmacies and 100 products, were still recording a 5% error rate at the end of last year after an original error level of 30%, according to EGA.   

Clearly once the FMD packaging rules start to come into force in 2018--seven years after the approval of the directive--the rules will still take time to provide a firm basis for a smooth and efficient process for end-to-end product verification. 

Manufacturers are taking measures to comply with new package safety rules.

European Union Packaging Safety Features Come into Effect

Gaining access to Europe’s pharmaceutical markets has become a multi-stage operation. The licensing of a new drug is only a preliminary step in what can be a lengthy and complex procedure for some pharmaceutical companies, particularly those with innovative biopharmaceuticals. First a drug has to be approved for its quality, safety, and efficacy by one or more regulatory authorities. This approval can be either by the central London-based European Medicines Agency (EMA) for a product to be marketed across the region or by a national licensing authority for one to be sold only in specific European countries.

To be made available, however, in the public sector health services a medicine has to be approved for reimbursement. These reimbursement decisions are increasingly determined by separate investigations of medicines often called Health Technology Assessments (HTAs). While the regulatory agencies deal with benefit-risk aspects of medicines, HTA bodies gauge their effectiveness in relation to existing products, particularly on the basis of cost.

The role of these assessments in European national pharmaceutical markets has become so important that EMA has agreed to collaborate with EUnetHTA, a European Union assessment network, on involving HTA bodies in giving advice to manufacturers in the early stages of a drug’s development. 

The move has been welcomed by small- and medium-sized enterprises (SMEs), especially those developing advanced medicines. “SMEs are generally interested in receiving joint EMA/HTA advice, in particular when it comes to advanced therapies,” says Paolo Morgese, chairman of the HTA Topic Group of EuropaBio, a biotechnology trade association. “This is not necessarily linked to the development of new manufacturing processes per se, but more to the need of identifying a common set of data requirements,” he added. 

EUnetHTA has been stepping up its efforts to achieve more consistency in the methodology and content of HTAs among the European Union’s 28 member states. The assessments, carried out by a range of public agencies and advisory bodies comprising key opinion leaders (KOLs), mainly comprise appraisals of clinical trial data to ensure that a medicine gives added therapeutic value. But they are also starting to cover types of formulation and manufacturing processes particularly when gauging cost effectiveness. National bodies do not always carry out assessments but they are also conducted by regional clinical and funding organizations within countries. Their support can be necessary for a drug to be put on local formularies.  


  As a result of cuts in healthcare costs due to post-recession austerity programs, favorable HTAs are becoming crucial to the successful market launch of pharmaceuticals in Europe. HTAs backing reimbursement can be vital for new innovative medicines but can also be important to biosimilars. 

Despite Europe being a pioneer in the development and commercialization of biosimilars, it has a fragmented market for the products with national health authorities following different policies for their reimbursement and inclusion in formularies. While the EMA has the central responsibility for licensing biosimilars in the EU, many states have been carrying out their own assessment of them.

Biosimilar filgrastim, for the treatment of neutropenia with a granulocyte colony-stimulating factor (G-CSF) analog, had by last year built up market shares ranging from 90–100% in the UK and Sweden and several Eastern European countries. In Belgium, however, the penetration was only 1%, Netherlands 27%, and Switzerland 40%, according to figures from IMS (1).

An European Generic Medicines Association (EGA) survey of national regulators in the EU pinpointed a number of obstacles to the uptake of biosimilars, including a perception of biosimilars being inferior to the originals, with doctors being reluctant to prescribe them because of  “hypothetical uncertainties in their safety and effectiveness” (2). 

Assessments have done a lot to boost biosimilars prescribing in some countries. “Prior to a pro-biosimilar initiative in Hungary the country had the lowest uptake of biosimilars in Central and Eastern Europe,” Ken Walsh, responsible for global pricing and market access at Sandoz Pharmaceuticals, the leading biosimilars unit of Novartis, said at an EGA biosimilars symposium in 2013 (1). “(Then) payers in Hungary recognized the need to incentivize biosimilars uptake.”

Prominent KOLs were recruited to endorse a pro-biosimilars white paper, which after being submitted to the country’s Ministry of Health, led to a reimbursement agreement for the products. By early 2013, the share of biosimilars in the Hungarian filgrastim market was 99%.


  In Denmark, selection of biosimilars available in the country’s health service is based not just on price but quality issues like stability, according to Walsh. This has helped to overcome concerns among Danish patients about production standards with biosimilars. Within less than two years, biosimilar somatropin, the growth hormone, rose from a market share of around 20% in the country to over half.

In Germany, one of Europe’s biggest markets for biosimilars, there have also been worries among patients and doctors about the quality and safety of biosimilars. As a result, doctors’ organizations, and insurers or sickness funds have combined to raise the uptake of biosimilars through assessment work and the introduction of prescription quotas. “In some regions the physicians’ associations together with the sickness funds have been very committed to making sure that doctors are fully aware of the quality and benefits of biosimilars,” says Bork Bretthauser, managing director of Pro Generika, Berlin, the German generic-drug and biosimilars association. There are still big differences in the penetration of biosimilars between German regions. With biosimilar erythropoietin (EPO), for example, in regions like Saxony and Bremen it has shares of over half while in Saarland the proportion is only around 15%, according to Pro Generika. “There is still a concern about variations in product characteristics between batches of the same biosimilar, whereas doctors need to be made aware that there are variations between batches of the original as well,” says Bretthauser. 

Across Europe, HTA bodies are taking different approaches to the issue of quality in products like biosimilars and other biopharmaceuticals. “The matter of quality is a new area for HTAs,” says Paul Catchpole, director of values and access at the Association of the British Pharmaceutical Industry (ABPI), London.  “Once a product like a biosimilar is assumed to have clinical equivalence to the original, there is a question about what evidence should be assessed for matters like comparative quality.”

The difficulties facing biosimilar producers with reimbursement and market access are those confronting all producers of new medicines in Europe with innovative production processes. Gaining positive HTAs and reimbursement decisions can be especially hard for SMEs with advanced therapy products and orphan medicines. Unlike with large drug companies, they do not have the resources to lobby assessment organizations.

Three years after its cartilage regeneration, biopharmaceutical ChondoCelect was approved by the EMA, TiGenix NV, Leuven,. Belgium, a cell-therapy specialist, has achieved reimbursement deals for the product in only three European countries--Belgium, Netherlands, and Spain, all of which it has facilities in.

“Gaining reimbursement approval has been much slower than expected,” says Maria Pascual Martinez, vice-president, regulatory affairs at TiGenix. “In the current economic conditions, securing access to health service patients is difficult, particularly when your technology can be regarded as being disruptive.”

Uniqure BV (Amsterdam) formed a partnership last summer with Chiesi Farmaceutici SpA (Parma, Italy), a specialist in the development and commercialization of rare disease therapies, to help gain reimbursement approvals for its Glybera medicine, an expensive orphan treatment for lipoprotein lipase deficiency (LPLD).  It was the first gene therapy to be approved by the EMA in November 2012. Important to the success of Glybera will be the efficiency of the process at its Amsterdam plant for producing gene cassettes for delivering transgenes into the body’s cells.  Chiesi’s strategy is to obtain reimbursement deals this year in the large European markets on a single price, likely to be a six-digit US-dollar figure, for a one-time treatment.

The big challenge for Chiesi and Uniqure is obtaining consistent HTAs on an orphan medicine, particularly on its cost effectiveness when there is little comparative evidence on issues like manufacturing efficiencies.

Producers of new drugs need more uniformity in assessments across Europe if they are to obtain the reimbursement prices they need to recoup their development costs.


  1. 	K. Walsh, “Biosimilars’ utilisation and the role payers do play in driving uptake in Europe: an industry perspective,” Biosimilar Medicines, 11th EGA International Symposium, London, Apr. 25-26, 2013.
  2.	EGA,

Survey to Members States and EEA Countries on Biosimilars 

(EGA, September 2012), accessed Jan. 16, 2014. 

 Sean Milmo is a freelance writer based in Essex, UK, 

High technology assessments are having an impact on biosimilars development in Europe.

EMA Collaborates with HTA Assessment Networks

Europe’s regulatory agencies have been stepping up their support for small- and medium-sized enterprises (SMEs), including micro companies, in an effort to stimulate more development of innovative medicines. The companies are being offered free or heavily discounted regulatory and administrative assistance, training sessions, evaluation, and above all, scientific advice that can raise the chances of a new medicine gaining marketing approval. 

The importance of early dialogue with regulators 


  Companies are encouraged to contact the agencies as early as possible during the drug-development stage to ensure that their manufacturing processes, in particular, will not lead to regulatory difficulties. It is, however, hard work for the regulatory agencies because many small companies (a high proportion of which are startups founded by individual specialists or small groups of scientists) tend to delay contacting the regulators until product development is close to the preclinical or clinical-trial stage. For the agencies themselves, the promotion of innovation can be a new role with which they need to become more familiar with to bridge any communication gaps with entrepreneurs.

 “The people running SMEs know the science and technology of the area in which they are doing business,” explains Hooshang Zavareh, founder of ChemPharmServe, Cambridge England, a company that specializes in drug-development services. “They often don’t see the need for help from regulators until they get to the point where they need to make a regulatory application. If they want outside help before then, they will go to a consultant.”

Nonetheless, the agencies believe that having much closer ties between themselves and entrepreneur innovators is essential. With Big Pharma cutting down on research activities, they believe much of the impetus behind innovation in medicines--at least in the early stages of development--will come from the companies with low turnovers and few employees, for example micro companies with less than 10 employees and annual revenues of less than €2 million (approximately $2.7 million), SMEs with not more than 50 personnel and annual turnovers not exceeding €10 million, and medium enterprises of less than 250 employees and an annual turnover of not more than €50 million.


  The European Union is currently calling SMEs “the powerhouse” of its Innovation Union, a concept behind its new seven-year €77 billion research program called Horizon 2020, which starts next year. Approximately 10% of the program’s budget will be allocated to healthcare, demographic change, and well-being. A major objective is the elimination of fragmentation in the fields of scientific research and innovation. Among the EU’s regulatory agencies in pharmaceuticals, the most active in championing innovation has been the European Medicines Agency (EMA), which is responsible for centralized approvals of medicines, including those based on novel technologies and orphan medicines.

SMEs make up a growing proportion of companies applying to the EMA for an initial evaluation of a new medicine, including its manufacturing process. Almost 30% of applicants in 2012 were SMEs, which also accounted for 68% of evaluation applications for orphan medicines compared to 27% in the previous year

In 2012, the number of SMEs registered with the agency rose 62% to 1098 mainly because of fees reductions and also because companies could make electronic submissions of product information. This year, the rate of increase has slowed down with the total registrations by late November going up only a further 12% to 1234. Of this total, 43% were micro-sized companies, 12% were academic spin-offs, and 5% of registrated SME companies had been created since January 2012. The registered SMEs had a total of approximately 3000 products under development.

Understanding the route to drug approval  


  “From a survey we did in 2011, we found that a lot of SMEs lack personnel with experience of bringing products through the regulatory system. As a result, they attach great importance to having early access to EMA,” says an agency official in an interview with 

 “Our figures show that those who do contact us early are more likely to be successful with a marketing-authorization application.”

One of the most highly valued services of the agency among SMEs has been the provision of scientific advice, available at a 90% discount, particularly on quality and process issues. “Quality documentation continues to be a problem area for many SMEs, particularly relating to manufacturing process validation, the setting of specifications, and stability data,” says the SME Office in its latest annual report (1). The agency’s SME Office has been disappointed with the low uptake of services from SMEs involved in the development of advanced therapy medicinal products (ATMPs)—such as gene therapy, somatic-cell therapy, and tissue engineering. SMEs have been accounting for 75% of EMA’s small number of ATMP approvals, for which there were only three applications last year.

To provide an incentive for more SMEs to develop advanced therapies, EMA has set up a scheme for the scientific evaluation and subsequent certification of the quality and, where necessary, non-clinical data of new products in the area. Certification should help ease the way to marketing authorization. Another attraction is that it should help companies obtain funding and license out their technologies. The quality data to be certified would include information on starting and raw materials, the manufacturing and characterization of the active substance, and the reproducibility of the manufacturing process for the medicinal product.


  By early this year, however, there had been only two applicants for certification, which prompted the EMA to conduct a survey to find out the reasons for the apparent lack of interest. Survey results showed that nearly two thirds of SMEs who answered questions on certification—amounting to only 21% of those surveyed—considered it to have positive advantages. EMA concluded from the study that participants seemed confused about the scope of certification, which indicated a need for the agency to clarify its role in the regulatory process. 

From EMA’s viewpoint, one big success story with its new relationship with SMEs has been the way it worked closely, from an early stage, with the Dutch start-up uniQure to enable its product alipogene tiparvovec (Glybera) to gain the EU’s first marketing approval for a gene therapy in late 2012. The product was developed for the treatment of lipoprotein lipase (LPL) deficiency. For the agency, the approval process was scientifically challenging because alipogene tiparvovec was a new type of medicine without any regulatory history. “The lessons learned from this case are multiple and it paved the way for approval of similarly complex medicines in the future,” said Christian Schneider, chair of the EMA’s committee for advanced therapies (CAT) and Hans-Georg Eichler, senior medical officer, in a joint article in the agency’s latest annual report (2).

EMA stresses that in its efforts to forge closer ties with SMEs, it is not trying to undermine the position of consultants and other experts in the pharmaceutical industry. Its role is not “to substitute the industry’s responsibility for the development of their products,” says the agency.

A similar point is being made by national agencies for medicines regulation, which have been setting up innovation offices to liaise with SMEs. So far, out of the 28 EU member states, agencies in Germany, France, UK, Sweden, and Finland have created SME units that have already formed themselves into a network to exchange experiences and best practices. 

In the UK, an Innovation Office, opened in March by the country’s Medicines and Healthcare Products Regulatory Agency (MHRA), is providing multi-disciplinary guidance on “novel development methodologies, manufacturing processes, or new materials that have not been previously used in either the pharmaceutical or device industries,” says Ian Hudson, the MHRA’s licensing division director.

The agencies are emphasizing that their units can be used by any SMEs developing an innovative product or process whatever regulatory procedure or route they intend to use. “We want to encourage SMEs to come to a regulator as soon as possible in the development work so that they get the production process right from a regulatory perspective early on,” explains Lars Dagerholt, head of the Innovation Office at the Swedish Medicinal Products Agency, Stockholm. “We also don’t mind them shopping around other agencies. These agencies can have different procedures and experts with different approaches.” The idea is to persuade SMEs that the regulatory mechanism is not as complex as it looks and above all, that the regulators are there to assist rather than hamper innovation. 


 Sean Milmo is a freelance writer based in Essex, UK, 

With SMEs gaining wider recognition as the powerhouse of research and innovation in Europe, regulatory agencies are urging companies to engage with regulators early in the drug-development process.

Early Communication with Regulators is Essential for SMEs

The European Union is strengthening its pioneering role in the regulation of biosimilars by further developing the basic rules for determining the levels of compatibility for this group of drugs. There are, however, some key issues that are not easy to resolve, as evident in a recent workshop on biosimilars organized by the European Medicines Agency (EMA). The meeting, held in October 2013, was called to consider issues raised by three of EMA’s revised guidelines on biosimilars, one covering general principles, the second on non-clinical and clinical matters, and the third on quality issues. The deadline for comments on the first two guidelines was the end of October, whereas for the third issue regarding quality, it was a year ago, indicating that despite the time lapse, there was still a need for further discussions to deal with the difficulties of publishing a final draft.

  The EU wants to keep ahead of the game in the regulation of biosimilars to give the region an advantage in establishing a large domestic market for the medicines. With the aim of helping to stimulate the global development of these medicines, the EU has opted for more flexibility in the choice of the original biopharmaceutical or reference product to which biopharmaceuticals will have to show comparability in quality, safety, and efficacy to be approved as biosimilars. 
  


  Revised guidelines on general principles 


  In its revised guidelines on the general principles for biosimilars, EMA states that the reference product must be a medicine authorized in the European Economic Area (EEA) (1). However, the EU also confirms that “it may be possible” for the biosimilar to be compared, “where needed,” with a non-EEA authorized product in clinical and non-clinical studies. Because the non-EEA authorized product would have to follow similar scientific and regulatory standards as those of the EMA, it would have to be in a country that is a member of the International Conference on Harmonization (ICH), according to the guideline. Also, the biosimilar applicant using the non-EEA route would have to provide bridging data from structural and functional analysis, and possibly from pharmacokinetic and pharmacodynamic studies, to show that the non-EEA drug was “representative” of the EEA reference product. Eugene Corretge, speaking on behalf of European Biopharmaceutical Enterprises (EBE), representing both makers of original biologics and biosimilars, said that the revised guideline was unclear about whether bridging data would be needed when a comparability study was conducted only partially or in totality with a non-EEA authorized medicine. 
  
Karl Heinz Emmert, vice-chair of the European Biosimilars Group (EBG), part of the European Generic Medicines Association (EGA), stated that the revised guidelines put forward “strong scientific principles” to support the use of non-EEA drugs sourced from ICH regions as reference products. There could be more consistency between products from different licensing jurisdictions than those from a single licensing jurisdiction, he explained. “Reference products from one original manufacturer and sourced from a different jurisdiction are often not distinguishable,” Emmert said. “A reference product supplied in one jurisdiction is often manufactured in different facilities.” Yet, it would not require non-clinical or clinical bridging studies, he added. 

Comparability of the reference products of one original manufacturer but from different jurisdictions could be established by similarity of quality based on stringent analytical and biological assays, explained Emmert. “Non-clinical and clinical studies are not suitable to establish differences between the ‘same’ reference products of one original manufacturer,” he said. “Analytical and biological assays are much more sensitive and are, thus, much more suitable.”
  
  


There was general agreement on a stepwise approach to establishing the necessary similarities between the biosimilar applicant’s drug and the reference product, which would effectively, in most cases, make non-clinical or clinical studies superfluous. Instead, the comparability exercise would be focused mainly on the manufacturing process, especially for more simple biosimilars.

“For structurally more simple biological medicinal products, a comparative clinical efficacy study may not be necessary if similarity of physicochemical characteristics and biological activity or potency of the biosimilar and the reference product can be convincingly shown,” said Martina Weise of the Federal Institute for Drugs and Medical Devices (BfArM), the German regulatory agency. In this respect, the drawing up of a quality target product profile (QTPP), which summarizes the required quality characteristics of the biosimilar, was regarded as being crucial. “It would be primarily based on extensive characterization data from the reference products,” explained Nicklas Ekman of the Finnish Medicines Agency. “It would be detailed at an early stage of development, forming the basis of the development of the biosimilar product and its manufacturing process.” 

Beverley Ingram, an EBE representative, said her association recommended reinforcing the role of the QTPP in a stepwise approach with it being quantitative by nature. However, setting quantitative, meaningful criteria is a technically complex topic, which she suggested should be investigated further in a reflection paper proposed by EMA on the use of statistics in comparing biological drugs, including biosimilars.

Joerg Windisch, EBG chair and chief science officer of Sandoz Pharmaceuticals, stressed that comparability between biosimilars and their reference products included having similar variabilities, particularly those between batches. “No batch of any biologic is ‘identical’ to other batches,” he explained. “Variability is natural even in the human body and is usually not problematic.”

Significant differences would be those that have a clinical impact, Windisch said. It is, therefore, important to have a systematic and quantitative assessment of quality attributes to pick out those that are crucial based on their clinical relevance. These critical attributes are one of the key elements that determine whether a drug is acceptable as a biosimilar, he said.

Another potential source of unacceptable incompatibilities is the use of contrasting expression systems in biosimilar proteins. Windisch pointed out that a distinction had to be made between different types of existing expression systems and those that are novel. Different kinds of existing systems could provide similar quality attributes. Also, because they have been applied for some time, these systems would have “equal or better” safety track records. On the other hand, novel expression systems were by definition unknown entities with an absence of safety data. “The use of expression systems with no safety record is a lot more challenging and is something you do not want to risk doing in the development of a biosimilar,” Windisch said. Differences in a drug that go beyond the range of variability in the reference product, particularly when they have clinical significance, are likely to be rejected as being a biosimilar by regulators. 

Workshop attendees were told about the complications of setting general limits on acceptable differences between biosimilars and reference products. “You cannot provide that sort of clarity,” said Weise. “It would be very difficult to set one margin that fits everything. These limits have to be set on a case-by-case basis.” 

In respect of an individual-item approach to products, some speakers pointed out that with some biosimilars, comparability should not be confined to the active substances. They should cover the whole formulation, including excipients and diluents because of their effect on the medicine’s safety and efficacy. A similar procedure was suggested for dealing with the issue of immunogenicity. “There are molecules on the market whose immunogenicity has not been established,” said Windisch. “It’s up to the applicant for authorization of a biosimilar to justify that no immunogenicity studies are necessary. In most cases, this seems to be unnecessary but we’ll have to see how the science develops on this issue.” Because of the relatively short history of biosimilars, there is a lack of knowledge about some of the important aspects of their safety. Hence, there is still a lot to be learned about how they should be properly regulated. 

Draft Guideline on Similar Biological Medicinal Products

Sean Milmo is a freelance writer based in Essex, UK, 

The European Union is strengthening its pioneering role in the regulation of biosimilars by further developing the basic rules for determining the levels of compatibility for this group of drugs. There are, however, some key issues that are not easy to resolve, as evident in a recent workshop on biosimilars organized by the European Medicines Agency (EMA).

Regulation of Biosimilars: A Matter of Variability, Similarity, and Comparability

The European Union is introducing a system for implementing standards of good manufacturing practices for medicine excipients after a long campaign for the imposition of GMP standards by excipient manufacturers in the region. The move follows the creation of new EU rules for GMP standards for imported APIs; full enforcement began this summer.

  The imposition of the two sets of GMP standards, which is laid down in the EU’s Falsified Medicines Directive (FMD), is seen by European manufacturers of active substances and excipients as necessary to stop the increasing numbers of substandard products imported into the EU in recent years, particularly from Asia.


  In addition to the GMP initiative with excipients, the EU has also been tightening up rules on other quality issues, such as the use of certain phthalate ingredients because of their possible adverse effect on human reproduction and development. The London-based European Medicines Agency (EMA), responsible for centralized pharmaceutical regulation in the EU, has been drawing up stricter rules on information of excipients in labels and product leaflets.  

Excipient manufacturers in Europe, while welcoming the tougher quality standards, reckon that the EU and national regulatory authorities are still not doing enough to encourage innovation, according to the International Pharmaceutical Excipients Council (IPEC). In particular, they are continuing to press for the introduction of an excipients master file system, the absence of which is putting the EU regulators out of line with those in the US, Canada, Australia, and other developed countries.

“There is a lot of regulatory activity in the EU at the moment with excipients with the objective of giving European producers more of a level playing field internationally,” explains Kate Denton, a regulatory affairs manager at Novozymes Biopharma UK Ltd., Nottingham, UK, a maker of biopharmaceutical excipients and part of the Danish-based Novozymes group. “Now is a good opportunity to do something about the lack of an excipients master file, which has become a barrier to innovation in Europe,” she tells 

On GMP for excipients, the European Commission has been finalizing details of a guideline after issuing a draft with a consultation period that ended in April of this year. The finalized version looks likely to be similar to the Quality Management System of the International Organisation for Standardisation (ISO 9001:2008) and to a joint guideline of IPEC and the London-based Pharmaceutical Quality Group (PQG).

Under the FMD approved two years ago, marketing authorization holders have to ensure that “the excipients are suitable for use in medicinal products by ascertaining what the appropriate good manufacturing practice is” (1). In the EU’s draft guideline, the quality risk management principles of the International Conference on Harmonisation (ICH) would be used to categorize the excipients as being of “low,” “medium,” or “high” risk to determine the appropriate GMP. This risk assessment would take into account the potential for microbiological or viral contamination and for impurities originating from raw materials.


Mechanisms are now being put in place for third-party auditing schemes generating single certificates covering both GMP and good distribution practice (GDP), which are acceptable to pharmaceutical manufacturers and the regulatory authorities in Europe.
  
  The main organizations carrying out the audits in Europe are likely to be the US-based Rx-360 International Pharmaceutical Supply Chain Consortium and EXCiPACT, Brussels.  EXCiPACT has been set up by four groups--IPEC, PQG, European Fine Chemicals Group (EFCG), and the Federation of European Chemical Distributors (FECC). So far the organization has certified two auditing organizations to carry out its audits with two excipient producers in Germany already receiving certificates and three others for European manufacturers close to being issued. The GMP standard being used by EXCiPACT is based on the ISO 2001 and IPEC-PQG guideline and will be broadly similar to the one being finalized by the European Commission. 

“We have got a momentum going,” says Tony Scott, a UK consultant working for EXCiPACT. “An acceptable third-party auditing system for issuing single certificates is essential if the EU’s requirement for GMP compliance is going to work. Otherwise excipient producers and suppliers will be overwhelmed with visits by auditors.” The third-party auditing system will cover mainly low- and medium-risk excipients and some high-risk ones. “We’ll be dealing with the 90% of excipients considered to be safe,” Scott told 


In a virtual category of their own are novel excipients whose ingredients, modes of action, or other aspects of their performance manufacturers want to keep confidential. Also regulators have to cope with an absence of other products with which to compare them in order to assess their safety.

The major impetus behind innovation in excipients is the need to help with problems like poor solubility, absorption, and stability of active substances. “The development of new molecular structures in excipients can be a big challenge for excipient producers because they have to finance their own toxicity and tolerance studies, which can be very expensive,” explains Professor Rainer Mueller, founder of Pharmasol, Berlin, a producer of solid lipid nanoparticle (SLN) excipients. “With classes of new chemical entities, excipient manufacturers are avoiding being the first ones on the market so that they have the responsibility to carry out the first safety studies,” he continued. “If you’re not the first, the costs would be lower.” 

Although marketed as nanoparticles, Pharmasol’s lipid particles fall outside the official EU definition of “nano” because they are larger than 100 nm. “If they were smaller we would also be required to carry out toxicity and other studies,” he said. 

Nonetheless, in a recent reflection paper, the EMA indicated that with nanoparticles falling within the EU definition and with other innovative excipient materials, there were possible advantages in not being the first on the market (2). This would particularly be the case if the product could be demonstrated to be similar to or a follow-on of a previously marketed product, the paper says.

“Formulation scientists prefer excipients that have a pre-approved functional role in drug products and a pharmacopeia monograph in order to avoid additional risks in the approval process,” says Francois Scheffler, head of global marketing pharma ingredients at BASF. “In this situation, it is typical for the transition from novel excipient to commonly accepted excipient to take from 7-10 years,” he adds. 

The European branch of IPEC believes that the commercialization timeframe for novel excipients would be much shorter if the EU accepted a system for excipient master files (3).  The files would consist of a closed part with confidential information accessible only to the regulator and an open part for the pharmaceutical manufacturer to enable it to ensure the efficiency, efficacy, and quality of the medicine. 

A direct approval process based on a master file system would “simplify the overall drug approval process and as a consequence accelerate drug development and, therefore, drug launches,” says Scheffler. “That would foster innovation and ultimately improve treatment options for patients,” he adds.

The EMA has set up a working group to investigate possible improvements to the EU master file system for active ingredients. IPEC and other groups argue that the system of master files for actives could be extended to cover excipients (3). 

The regulatory authorities acknowledge the arguments in favor of an excipient master file procedure but argue that the introduction of one is not a priority since improvements to other parts of the approval process are more urgent. Excipient producers, however, point out that novel excipients hold the key to making a wider range of drug more beneficial to patients by enhancing their delivery capabilities. “The European authorities are out of sync with the rest of the world with efforts to encourage innovation through harmonization of procedures,” says Denton. 


  1.	EC, Directive 2011/83/EC, article 46(f).
  2. 	EMA, Reflection Paper on Surface Coatings: General Issues for Consideration Regarding Parenteral Administration of Coated Nanomedicine Products, EMA/325027/2013.
  3.	IPEC Europe, 

IPEC Europe Approach to the Lack of a Master File System for Excipients in Europe


Sean Milmo is a freelance writer based in Essex, UK, seanmilmo@btconnect.com.

Regulators hope new standards will stop illegal drug imports, but manufacturers fear they may stifle innovation.